有限采样法估算口服托烷司琼药时曲线下面积模型的建立和验证

Establishment and validation of models for estimating the area under the concentration-time curve of tropisetron using limited sampling strategy

目的建立有限采样法估算口服托烷司琼药时曲线下面积(AUC0-t)的模型,并对该模型进行验证。方法采用2周期双交叉的试验设计,20名健康志愿者口服托烷司琼参比制剂和受试制剂20mg,LC-MS/MS法测定各采样时间点托烷司琼的血药浓度。以参比制剂血药浓度数据作为建模数据,以稀疏血药浓度数据点建立多元回归数学模型,估算AUC0-t。采用内部、外部数据结合Monte Carlo模拟技术对模型进行验证和模型敏感度和稳定性评价。结果给药后8h和24h血药浓度(c8、c24)数据点预测AUC0-t的回归模型的线性关系最佳(r2=0.99,平均预测误差<1%、平均绝对误差<5%)。验证结果表明:c8,c24估算AUC0-t的准确性较好(平均预测误差<8%、平均绝对误差<7%),AUC0-t预测误差超过±20%的样本数<5%。结论有限采样法估算口服托烷司琼AUC0-t准确性好,适用于该药的药动学和药效学研究。

Purpose To establish and validate the models for estimating the area under the concentration-time curve （AUC0-t） of tropisetron using limited sampling strategy （LSS）. Methods Twenty healthy subjects received a single 20 mg oral dose of tropisetron, as reference or test formulation, at a 14-days interval, in a randomized, crossover protocol. Plasma concentrations of tropisetron, measured by mass spectrometry, were employed to develop LSS models. A multiple linear regression analysis of the AUC0-t, against the tropisetron concentration for the reference formulation was carried out to develop LSS models. The models were validated and evaluated by internal and external data combining with Monte carlo simulation. Results Linear regression analysis of the AUC0-t, and a jackknife validation procedure revealed that models based on two sampling times （8 h and 24 h） predict accurately （r2 = 0.99; bias〈1%; precision〈5%）. Validation tests indicate that the prediction of the proposed model is accurate and reproducible （bias〈8%; precision〈7%）. The prediction error of AUC0-t, beyond 20% was less than 5 %. Conclusions The 2-point LSS models developed in the current study could accurately predict the AUC of tropisetron under a variety of experimental conditions and, thus, may be valuable for exploring the relationships between the pharmacokinetics and pharmacodynamics of this 5-HT antagonist, at reduced costs of sample acquisition and analysis.